The present invention relates to biologically active compounds which are N-alkyl-substituted derivatives of aminotetralin, and to their therapeutic applications.
Many compounds are known which exhibit adrenergic effects by which term is mean generally a stimulation of nerve fibers mainfested, for example, by nervousness and palpitation.
In 1948, Ahlquist, Am. J. Phyisiol. 135, 586 (1948), demonstrated that the effects of adrenergic drugs appeared to be mediated through two different receptor systems, for which he proposed the names of .alpha.- and .beta.-adrenergic receptors. The .alpha.-adrenergic receptor was associated mainly with excitatory functions, such as vasoconstriction and stimulation of the uterus, nictitating membrane, ureter, and dilator pupilae, plus an inhibitory function (intestinal relaxation). The .beta.-adrenergic receptor was held to be associated mainly with inhibitory functions, characterized by smooth muscle relaxation in the respiratory tract, uterus, ciliary muscle, and blood vessels in skeletal muscle and liver, plus an important excitatory function, viz. myocardial stimulation.
Lands et al., Nature 214, 597 (1967) demonstrated that .beta.-adrenergic effects can be further subdivided into .beta..sub.1 and .beta..sub.2 adrenoreceptors. Of these, the .beta..sub.1 function includes production lipolysis and cardiac stimulation, indicated by an increase in force and rate of myocardial contraction, and the .beta..sub.2 function is indicated by production of bronchial dilatation and vasodepression.
The biological activities of a series of dihydroxy aminotetralins, including the production of emesis in pigeons and dogs, and gnawing in mice, were studied by Cannon et al., J. Med. Chem. 15, 348 (1972). Some of these compounds were found to produce an adrenergic effect similar to that produced by dopamine, 4-(2-aminoethyl)-catechol, namely, to activate dopaminergic receptors. Among the compounds tested was 2-N-methylamino-1,2,3,4-tetrahydro-5,6-dihydroxynaphthalene, in the form of its hydrobromide salt, administered parenterally. However, the only effects noted were the so-called dopaminergic effects, i.e. mouse gnawing, pigeon compulsive pecking response, pigeon and dog emesis.
Further study of certain 2-aminotetralins from the standpoint of their activity as dopamine receptor agonists, was reported by McDermed et al., J. Med. Chem. 18, 362 (1975). The term agonist refers generally to a muscle directly engaged in contraction as distinguished from muscles which have to relax at the same time. Among the derivatives investigated was 2-N-n-propylamino-1,2,3,4-tetrahydro-5,6-dihydroxynaphthalene, the HCl salt of which was reported as melting with decomposition at 231.degree.-233.degree. C. Among the various mono- and di-(lower) alkyl amino derivatives studied, those most consistently productive of apparent dipaminergic activity were the di-n-propylamine derivatives.
Isoproterenol (3,4-dihydroxy-.alpha.-[isopropylamino) methyl]-benzyl alcohol is known as sympathomimetic bronchodilator which may produce adrenergic effects. It is widely used because of its rapid onset of action by inhalation. However, in effective dosages, isoproterenol usually activates all .beta.-receptors and often causes cardiac effects because of its ready absorption. It is rapidly taken into cells, and in the lungs (and perhaps elsewhere) it is metabolized by the enzyme catechol-O-methyl transferase, to 3-methyl-isoproterenol, which latter compound is a weak but definite adrenergic .beta.-blocking agent. When isoproterenol is administered orally it is additionally inactivated in the digestive tract and the liver by conversion to a sulfate derivative, which accounts for its relatively short duration of action.